The Management of Acute Venous Thromboembolism in Clinical Practice – Study Rationale and Protocol of the European PREFER in VTE Registry Giancarlo Agnelli1, Anselm K

Agnelli et al. Thrombosis Journal (2015) 13:41 DOI 10.1186/s12959-015-0071-z

ORIGINAL CLINICAL INVESTIGATION Open Access The management of acute venous thromboembolism in clinical practice – study rationale and protocol of the European PREFER in VTE Registry Giancarlo Agnelli1, Anselm K. Gitt2, Rupert Bauersachs3,4, Eva-Maria Fronk5, Petra Laeis5, Patrick Mismetti6, Manuel Monreal7, Stefan N. Willich8, Wolf-Peter Wolf4, Alexander T. Cohen9* and On behalf of the PREFER in VTE investigators

Abstract Background: Venous thromboembolism (VTE) is a major health problem, with over one million events every year in Europe. However, there is a paucity of data on the current management in real life, including factors influencing treatment pathways, patient satisfaction, quality of life (QoL), and utilization of health care resources and the corresponding costs. The PREFER in VTE registry has been designed to address this and to understand medical care and needs as well as potential gaps for improvement. Methods/design: The PREFER in VTE registry was a prospective, observational, multicenter study conducted in seven European countries including Austria, France Germany, Italy, Spain, Switzerland, and the UK to assess the characteristics and the management of patients with VTE, the use of health care resources, and to provide data to estimate the costs for 12 months treatment following a first-time and/or recurrent VTE diagnosed in hospitals or specialized or primary care centers. In addition, existing anticoagulant treatment patterns, patient pathways, clinical outcomes, treatment satisfaction, and health related QoL were documented. The centers were chosen to reflect the care environment in which patients with VTE are managed in each of the participating countries. Patients were eligible to be enrolled into the registry if they were at least 18 years old, had a symptomatic, objectively confirmed first time or recurrent acute VTE defined as either distal or proximal deep vein thrombosis, pulmonary embolism or both. After the baseline visit at the time of the acute VTE event, further follow-up documentations occurred at 1, 3, 6 and 12 months. Follow-up data was collected by either routinely scheduled visits or by telephone calls. Results: Overall, 381 centers participated, which enrolled 3,545 patients during an observational period of 1 year. Conclusion: The PREFER in VTE registry will provide valuable insights into the characteristics of patients with VTE and their acute and mid-term management, as well as into drug utilization and the use of health care resources in acute first-time and/or recurrent VTE across Europe in clinical practice. Trial registration: Registered in DRKS register, ID number: DRKS00004795 Keywords: Venous Thromboembolism, Anticoagulation, Vitamin K antagonists, Novel Oral Anticoagulants, Prevention, Registry

* Correspondence: [email protected] 9King’s College, Guys and St Thomas’ Hospitals NHS Foundation Trust, Westminster Bridge Road, London SE1 7EH, UK Full list of author information is available at the end of the article

© 2015 Agnelli et al. Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Agnelli et al. Thrombosis Journal (2015) 13:41 Page 2 of 13

Background problems including a delayed onset of antithrombotic Acute venous thromboembolism (VTE), including deep- action; a narrow therapeutic window that requires close vein thrombosis (DVT) and pulmonary embolism (PE) is laboratory monitoring using the INR; an unpredictable a common disorder with an annual incidence of approxi- and variable pharmacological response; and food and mately 1 or 2 cases per 1000 persons in the general drug interactions requiring frequent monitoring and population [1–3]. Patients with DVT and PE have in- dosage adjustment [10]. creased morbidity and mortality both related to these Recently developed oral anticoagulants that are di- conditions and also associated co-morbidities such as rected against factor Xa or thrombin (factor IIa) over- cancer, medical conditions and surgical procedures [4]. come some limitations of standard therapy including the The main objective of anticoagulant therapy for patients need for injections of parenteral anticoagulants and for with acute VTE is to prevent thrombus extension, regular dose adjustments on the basis of laboratory embolization and recurrences. According to current monitoring [11–13]. However, VKAs are still often pre- practice guidelines the management of patients with acute scribed and although NOACs are widely approved in VTE consists of an initial treatment with bodyweight- Europe, use of NOACs is limited by national guidelines adjusted subcutaneous low molecular weight heparin and reimbursement. In Europe, little is known about (LMWH); adjusted-dose intravenous or fixed dose sub- which factors influence the individual VTE patients’ cutaneous unfractionated heparin (UFH); or bodyweight- utilization of health care resources and the correspond- adjusted subcutaneous fondaparinux followed by long- ing costs derived in hospitals, out of hospitals or in spe- term treatment with a vitamin K antagonist (VKA) or cialized centres during the period between confirmed non-VKA oral anticoagulants (NOACs) [5]. For the treat- first-time or recurrent VTE treatment and 12 months of ment of PE the current 2014 European Society of Cardi- follow-up. ology Guidelines on the diagnosis and management of acute PE recommend the use of NOACs as alternatives to Study aims VKAs [6]. The key aims of the PREFER in VTE registry were to Patients should receive parenteral anticoagulants (ei- assess the real-life acute and mid-term management of ther LMWH or UFH or fondaparinux) for at least five patients with VTE, the use of health care resources, and days. It is recommended to start VKA on the first treat- to provide data to estimate the costs for 12-months ment day because of the slow onset of action. LMWH, treatment following a first-time and/or recurrent VTE UFH, or fondaparinux therapy may be discontinued diagnosis in hospitals or specialized centers in Europe. when the VKA has reached its therapeutic level as indi- In addition, existing anticoagulant treatment patterns, cated by an international normalized ratio (INR) ≥2at patient pathways, clinical outcomes, treatment satisfac- two or more measurements at least 24 h apart. VKA tion, and health related quality of life (HR-QoL) were therapy should be continued for at least 3 months. For documented. most patients with a DVT and/or PE secondary to a transient risk factor the currently recommended dur- Primary objectives ation of treatment is sufficient, although extension by The primary objective of this registry was to assess the another 3 to 6 months of therapy may be indicated in 12-months direct healthcare resource use and to provide some patients [3]. However, for those with unpro- data to estimate the costs following an acute first time voked DVT or PE, the recommendation is to evaluate or recurrent VTE. In addition, detailed insights into the the risks and benefits for prolonged therapy. In either patients’ characteristics, the management of acute VTE case, the VKA dosage regimen needs to be adjusted (in particular DVT and/or PE) with specific focus on to maintain the INR in the therapeutic range (target prevention of VTE recurrences and its treatment-related 2.5, range 2.0 to 3.0). events such as bleeding, recurrence of DVT/PE, myocar- VKAs (such as the coumarins: warfarin, acenocou- dial infarction, stroke, systemic embolic events, post marol or phenprocoumon) are indirect coagulation in- thrombotic syndrome, cardiovascular (CV) events, and hibitors, which act by blocking the vitamin K-dependent death were collected. DVT was defined as DVT alone liver synthesis of the plasma coagulation factors II, VII, and PE as PE with or without DVT. IX and X. They were the only oral anticoagulants available for over 50 years. Randomized controlled trials have Secondary objectives shown that warfarin, the most commonly used VKA, The secondary objectives of this study were to 1) de- targeted to an INR between 2.0 and 3.0, reduces the risk scribe the treatment satisfaction, HR-QoL, and clinical of recurrent venous thromboembolic complications in outcomes following first time or recurrent VTE; 2) to subjects with DVT or PE by 80% to 90% [5,7–9]. How- explore the potential relationships between different an- ever, the use of VKAs is complicated by several inherent ticoagulants and duration of therapy, resource use, Agnelli et al. Thrombosis Journal (2015) 13:41 Page 3 of 13

estimated costs, treatment satisfaction, HR-QoL, and treating physician. All medication was prescribed in the clinical outcomes; 3) to explore possible geographic vari- usual standard of care and was not provided by the ations in the management of VTE patients, duration of study sponsor. Participation in the study in no way influ- therapy, resource use, estimated costs and treatment enced payment or reimbursement for any treatment satisfaction. received by patients during the study. Patients were free to withdraw from the registry at any time. Methods and design The PREFER in VTE registry was a prospective, observa- Selection of sites tional, multicenter study with a follow-up of 12 months Investigator sites were representative for the specific and enrolled 3,545 consecutive patients who gave local distribution of primary and secondary care settings informed consent from 381 centers (311 active centers in each participating country. A sufficient number of enrolling ≥1 patient) in seven European countries sites were identified including hospitals and specialized including Austria, France, Germany, Italy, Spain, centers to best represent current practice of VTE diag- Switzerland, and the UK between January 2013 and July nosis and treatment in each particular country. Most 2014. Data were recorded at baseline of the acute VTE centers contacted for participation were randomly se- and prospectively documented during follow-up at 1, 3, lected, others were chosen from experienced centers 6 and 12 months (Fig. 1). and all centers were asked to provide institutional de- Patient information was collected from two different tails in a short site feasibility questionnaire before be- sources: collection of baseline data took place in the ing selected. Each active site consecutively recruited hospitals or specialized centers at the time of the diag- at least 1 and up to 60 patients. The enrollment nosis of the acute VTE. Hospitals or specialized/primary period was 12 months. care centers could also opt to follow-up the patients at 1 month. As hospital based investigators do not always see the patient during the following 12 months as part of Selection of patients the routine clinical care, patients were followed by tele- Patients from Austria, France, Germany, Italy, Spain, phone calls. Patients agreed to provide contact details Switzerland and the UK who gave written informed con- for the planned follow-up calls with the permission to sent were consecutively enrolled into the registry in hos- hand the contact details over to the respective local con- pitals or specialized centers if they were at least 18 years tact research organization (CRO). old, had a confirmed first time or recurrent symptomatic This registry was conducted in accordance with the VTE defined as either distal or proximal DVT, PE [3] or Declaration of Helsinki and adheres to the principles of both, provided telephone contact details for follow-up Good Epidemiology Practice, and applicable regulatory calls, and were not simultaneously participating in a requirements. The responsible ethics committees of the double blind interventional study. participating countries and the hospital-based institu- We expect the parameters measured will vary between tional review boards approved the protocol of this regis- patients on the conventional pathway of treatment and try. Patients enrolled into this registry provided written those using NOACs and therefore the comparison be- informed consent. Due to the nature of a non- tween those following the conventional pathway and interventional registry, no specific treatments, tests, or those on the NOACs and the impact of NOACs on procedures were mandated or withheld from the QoL, Resource consumption and mostly health care patients. Treatment pattern and treatment initiation, utilization will be examined. continuation or changes were solely at the discretion of The study aimed to a achieve a general ratio of the physician and the patient. There was no attempt to PE:DVT which was approximately 2:3 resulting in a influence the prescribing patterns of any individual total number of PE (with or without DVT) patients

Fig. 1 Time course of the data collection from baseline to 12 months follow-up Agnelli et al. Thrombosis Journal (2015) 13:41 Page 4 of 13

of n = 1,399 and a total number of patients with DVT Quality of Life Questionnaire (EQ 5D–5L) (distal or proximal) of n = 2,056 (Fig. 2). EQ 5D-5L is a standardized measure of health status developed by the EuroQol Group in order to provide a simple, generic measure of health for clinical and Documented variables economic assessment [14]. Applicable to a wide range The enrolling study site documented all patient related of health conditions and treatments, it provides a baseline data at the time of the acute VTE. The follow- simple descriptive profile and a single index value for up calls were performed centrally by local CROs. The health status that can be used in the clinical and eco- CROs used standardized questionnaires to get all re- nomic evaluation of health care as well as in popula- quired information (i.e. recurrence of VTE, bleeding, tion health surveys. post-thrombotic syndrome, death, hospitalization, as well as medications and treatments, QoL and patient Treatment Satisfaction Questionnaire satisfaction (Perception of Anticoagulant Treatment Anticoagulation-specific questionnaire PACT-Q. The Questionnaire 2 [PACT-Q2], Venous Insufficiency Epi- ‘Perception of AntiCoagulant Treatment Questionnaire’ demiological and Economic Study [Veines-QoL/Sym] or was developed to assess patients’ expectations of, and Pulmonary Embolism Quality of Life [PEmb-QoL]), re- satisfaction with their anticoagulant treatment [15–17]. source consumption / health care utilization). Patient diaries were distributed to facilitate the standardized Veines-QoL/Sym structured phone calls. The treatment satisfaction questionnaire (PACT-Q2), the disease specific questionnaire The Veines-QoL/Sym is a patient-based questionnaire (PEmb-QoL or Veines-QoL/Sym) and the QoL question- designed for self-completion and measures the impact of ’ naire (EQ 5D–5L) were filled out at baseline, and re- DVT on symptoms and QoL from the patient s perspec- peated by post at 1, 3, 6 and 12 months after first tive; this was only completed by patients with DVT [18]. diagnosis of acute VTE. Table 1 displays the variables documented at baseline PEmb-QoL and at the follow-up visits at 1, 3, 6 and 12 months. The The PEmb-QoL questionnaire was modeled on the QoL data sources used in this study were clinical records, after DVT (Veines-QoL/Sym) questionnaire. This ques- self-reports, claims, and data from telephone interviews. tionnaire, like the Veines-QoL/Sym, assesses the frequency of symptoms, the time of day which the complaints are their worst, and activities of daily living, Patients’ treatment satisfaction and quality of life as well as work-related problems. However, the PEmb- Data on patients’ treatment satisfaction and QoL were QoL questionnaire is distinct from the Veines-QoL/Sym documented using specific patient-questionnaires. The in the inclusion of pulmonary-specific symptoms, adding following questionnaires were part of the evaluation: questions on limitations in daily physical activities, and

Fig. 2 Patient enrollment Agnelli et al. Thrombosis Journal (2015) 13:41 Page 5 of 13

Table 1 Data documented at baseline and at 1, 3, 6 and 12 months follow-up Variable Baseline Follow Up Month 1 Month 3 Month 6 Month 12 Eligibility criteria (1) X Baseline information (2) X VTE risk factors and comorbidities (3) X Baseline information on VTE (4) X VTE therapy (5) XXXX X Current and previous treatment for prevention of stroke and other thromboembolic events (6) XXXX X Quality of life (7) XXXX X Patient satisfaction (8) XXXX X PEmb-QoL Questionnaire (only PE-patients) X X X X X Veines-QoL/Sym Questionnaire (only DVT-patients) X X X X X Resource utilization (9) XXXX X Clinical events and hospitalizations (10) XXXX X Number of days in hospital, work days lost due to VTE, need for nursing/informal help X X X X X Legend (1) Objectively confirmed first-time or recurrent VTE; age ≥ 18 years, written informed consent (2) (Socio-) demographic variables: age, gender, height, weight, BMI, blood pressure, graduation, education, employment status, insurance status (3) Major surgery, bleeding history medical illnesses, multiple trauma, hip fracture, lower extremity paralysis, previous VTE, increasing age, cardiovascular or respiratory failure, prolonged immobility, presence of central venous illness, estrogens, wide Varity of inherited and acquired hematological conditions, cancer, chemotherapy etc (4) Date of first diagnosis, lead symptoms, diagnostic pathways, severity (5) Thrombolysis, Heparin, Vitamin K Antagonist, Embolectomy, Catheter, Insertion of V.cava filter (6) Physician’s clinical impression of the risk of stroke/ thromboembolic events; physician’s use of algorithm to determine risk; current anticoagulation (by drug, with information on continuation after the visit); discontinued anticoagulation (last 12 months); (Relative) contraindications to anticoagulation; INR (target and achieved value, frequency of tests, percentage of values within target range) D (7) EQ-5D (8) PACT-Q2 (9) Number of physician contacts (own office, other physicians); VTE related productivity loss and costs; number and type of VTE diagnostic tests since last visit /call (10) Specifically due to: VTE, stroke, acute coronary syndrome including myocardial infarction, arterial embolism, decompensated heart failure, syncope, bleeding events extending the number of questions on emotional func- Thirdly, prior to the creation of the analytic dataset, tioning [19]. more extensive quality control processes were per- The PEmb-QoL was only filled out by patients with formed. These checks, programmed in SAS (release 9.2 PE. or higher; Cary, NC, USA), included parent–child edits, consistency edits, and data transformations that facili- Data management and quality control tated analyses. Data entry was performed by the physician or study nurse via a secure website directly into an electronic Sample size database. This approach allowed online checks for In order to provide meaningful data on reimbursement plausibility and integrity. from different agencies in each participating country, There were three strategies for data quality checks: and because significant variation was expected between validations that occurred at the time of data entry countries, special care was taken to determine a suitable (i.e., “front-end”), a second, more sophisticated quality sample size of patients for each country. As costs are control program that ran as a prelude to the creation difficult to determine directly and are mostly triggered of the analysis data set and on-site data monitoring by the hospitalization of the patients, the sample size by the CRO. calculation was based on the rate of adverse events Front-end data checks are advantageous because mis- (AEs) leading to, or prolonging, hospitalization. takes are caught and corrected at the time of entry. Cer- Assuming a rate for the AEs that are leading to or tain data elements can be required, while other elements prolonging hospitalization and an absolute precision Δ, may allow missing values. Additionally, parameters were the sample size N is calculated which is needed if the re- defined to allow entry of only those records that met the spective 95% confidence interval (CI) should have a inclusion criteria. length/precision of 2Δ (±Δ). Concretely, for DVT a Agnelli et al. Thrombosis Journal (2015) 13:41 Page 6 of 13

hospitalization rate of 12.3% was assumed [15], while for country or by region. Patients violating any inclusion/ex- PE a hospitalization rate of 17.9% was taken [16]. Fur- clusion criteria were identified and documented. There thermore, for DVT as well as for PE, a relative precision were several variables of interest for additional analyses of 25% was assumed which corresponded to an absolute including: gender, age, weight, diabetes. Details on the precision of 0.031 for DVT and an absolute precision for selection criteria used were given in the statistical ana- PE of 0.045. Based on these assumptions a minimum of lysis plan and in the statistical section of the report. 432 evaluable DVT patients were needed while for PE a As the registry was exploratory in nature, and no minimum of 279 evaluable patients were needed hypothesis testing was conducted, there were no signifi- (Table 2). Taking into account a dropout rate of 20% and cance levels to be adjusted, and there was no require- being aware of the fact that DVT and PE patients were ment to provide stopping rules for the study. recruited in a ratio of 3:2 (DVT: PE), this resulted in a The statistical analysis was performed using SAS total of 900 patients recruited (= 540 DVT patients + (release 9.2 or higher; Cary, NC, USA). 360 PE patients) in each region and 4,500 patients in the overall registry. The above sample size consideration is Discussion taken from the observational plan and was made before Little is known about populations of unselected patients the start of the study. The primary parameters of interest with VTE. In Europe there is only minimal data describ- were the “costs” and the “rate for AEs leading to or ing individual patient characteristics, management pat- prolonging hospitalization” was taken as the main trigger terns, factors influencing health care resource utilization for this very general parameter. Therefore, the sample size and the corresponding costs. For completeness these consideration should be taken as a general guidance and data need to be derived from confirmed cases within needs to be interpreted in a flexible way. Based on real-life hospitals, out of hospitals, in primary care or in special- experience, in general a sample of ~600 patients is consid- ized centers. The critical period for recurrences and ered as robust enough for reliable cost estimations. bleeding is the time between first diagnosis and the following 12 months. Including unselected patients with Statistical analysis both first time and recurrent VTE allows the burden of This registry collected data under real life conditions. disease to be quantified. The statistical analysis was performed in an explorative The PREFER in VTE registry will help to get a detailed and descriptive way. All variables collected in the elec- insight into the characteristics and management of pa- tronic case report form as well as the data obtained from tients with VTE (DVT and/or PE) with focus on preven- the QoL assessments and all derived parameters were tion of events (bleeding, recurrence of DVT, recurrence used in the statistical analysis. of PE, post thrombotic syndrome, CV events, other Binary, categorical, and ordinal parameters were sum- complications and death) in a real life setting. Data were marized by means of absolute and percentage numbers collected from VTE patients during the acute event and within the various categories. followed by an observational period of up to 1 year and Numerical data was summarized by means of standard were used to assess direct healthcare resource use and statistics (i.e. number of available data, number of miss- estimated costs following acute first-time or recurrent ing data, mean, standard deviation, minimum, median, VTE. Patients were therefore treated on the discretion of maximum, lower and upper quartile). the physician in charge according to their regular med- Time-to-event variables were analyzed via a Cox pro- ical care. portional hazard regression model presenting hazard ra- In the past, most of the published information on the tios and the corresponding 95% CIs. No formal statistical current therapy and natural history of patients with VTE tests were performed within the statistical analysis. comes from randomized clinical trials, with strict inclu- A biometrical report using descriptive statistics of all sion and exclusion criteria, fixed doses of anticoagulant documented parameters was used to describe the overall drugs, and limited follow-up, mostly focused to obtain patient population as well as for each participating data on efficacy and safety. However, a number of

Table 2 Sample size calculations Assumed rate Assumed absolute precision Sample Sample of AE leading to, (relative precision) size (without size (including or prolonging, drop-outs) drop-outs) hospitalization DVT 0.123 0.031 (± 25%) 432 540 PE 0.179 0.045 (± 25%) 279 349 Sample size (for each region) for the assumed rate of AEs leading to, or prolonging hospitalization 0.123 (DVT) and 0.179 (PE) in order to achieve an absolute precision of 0.031 (DVT) and 0.045 (PE) for a two-sided 95% CI. (Based on normal approximation, calculated by nQuery Advisor® 7.0.). AE, adverse event Agnelli et al. Thrombosis Journal (2015) 13:41 Page 7 of 13

patients with VTE are never recruited in clinical tri- or physician, cardiologist and/or hospital) as well as als, particularly, the very young, the very elderly, the diagnostic pathways pregnant, those with multiple comorbidities, those 4. Drug utilization/use pattern of drugs for treatment with a high risk of bleeding and those with polyphar- of VTE and prevention of related events macy. Also there is scarce information on the current 5. Health related quality of life including patient therapy in real life (drugs, doses, duration and ap- satisfaction and real-world assessments of quality proach to patients with VTE recurrences and/or of life bleeding complications). There is also limited infor- 6. Resource consumption/Health care utilization. mation regarding the QoL, utilization of resources, costs, satisfaction of the patient and influence of their Conclusions willing on the duration of therapy. This information The PREFER in VTE registry will provide valuable in- may be very useful for patients, clinicians, healthcare sights into all these factors in patients with VTE and providers, health technology assessors and to the their acute and mid-term management. The study will pharmaceutical industry, who will all benefit from the provide the opportunity to identify differences in man- data about many aspects of VTE not previously con- agement and outcomes across care settings, and will sidered in detail in a broad unselected population. offer clarity relating to the effectiveness of anticoagula- Currently, PREFER in VTE is the only registry evalu- tion treatment strategies to treat acute VTE and to pre- ating the management of acute VTE in Europe; on an vent recurrent VTE events. international level, the management of acute VTE has been assessed in the RIETE registry and in the on- Appendix going GARFIELD-VTE registry [20,21]. List of PREFER in VTE investigators. The observational PREFER in VTE registry aims to address these questions by describing the current anti- Austria coagulant treatment patterns, pathways of clinical care, Marianne Brodmann, Peter Rief, Universitätsklinikum clinical outcomes as well as patient’s treatment satisfac- Graz, Graz; Lisbeth Eischer, Slagjana Stoshikj, tion and HR-QoL in a real world setting. Real life data Medizinische Universität Wien, Wien; Michael Hirschl, are of utmost importance to collect information on the Serge Weinmann, Landesklinikum Zwettl, Zwettl; Peter safety, efficacy and drug utilization of any novel drug Marschang, Universitätsklinik Innsbruck für Innere and to link the data with the regulatory mandated phase Medizin, Innsbruck. III data. This is an important stage in the observation and stringent control of all novel drugs. Therefore, there France is a need for a European Union wide, international ob- Fabrice Abbadie, Centre hispitalier Jacques Lacarin, servational registry of VTE patients treated in everyday Vichy; Antoine Achkar, CHI Eure et Seine – Site de clinical practice to provide complementary data to that Vernon, Vernon; Azeddine Addala, Perrone Reynaldo, from the trials and to fully understand the treatment Lyon; Frédéric Adnet, Hopital Avicenne, Bobigny; Jean- pathway of patients. François Alexandra, Hopital Bichat Claude Bernard, This large, European registry of acute VTE patients Paris; Sandro Aquilanti, Espace ARTOIS Santé, Arras; allows the opportunity to answer several research ques- Abdelkader Belhassane, Centre Hospitalier de Cambrai, tions that have not previously been investigated within a Cambrai Cedex; Anne Benaroya, Pole Sante Des Aspres, non- randomized, non-selected population. These ques- Thuir; Toufek Berremili, Marie Chevallier Grenot, CH tions will address the following six areas: Annecy Genevois, Pringy Cedex; Virginie Birr, Daniela Holtea, CHU Emile Muller, Mulhouse Cedex; Christophe 1. Patient characteristics of consecutive patients with Bonnin, Le Gibraltar 10–12, Nice; Frederic Bosler, 19 rue acute VTE in clinical practice including Robert Schumann, Sarrebourg; Marie-Gabrielle Bresin comorbidities, history of thromboembolic/bleeding Durand, Résid des remparts 7 rue des lombards, events, temporary and permanent risk factors Hennebont; Dominique Brisot, Centre Commercial La including severe medical disorders and interventions Croisee, Clapier; Christophe Brousse, Tarodo De La with VTE risk Fuente, Clinique Du Parc, Castelnau-le-Lez; Richard 2. Diagnosis of acute VTE (first-time [initial] or Cayman, 8 rue des des de l'aire, Bourgoin Jallieu; recurrent) including timing, symptoms and signs, Michèle Cazaubon, 17, rue Mesnil, Paris; Olivier clinical status and severity Champion, 6 Avenue Georges Pompidou, Chalon-sur- 3. Patient pathways including referral details and Saône; Myriam Chanut, Immeuble Le Clos de related time intervals (from primary to secondary Bellande, Aubenas; Pascal Chevalet, Hopital Bellier, care, e.g., internist, hematologist, vascular surgeon Nantes; Jerome Connault, Cecile Durant, CHU Hôtel- Agnelli et al. Thrombosis Journal (2015) 13:41 Page 8 of 13

Dieu de Nantes, Nantes; Joel Constans, Hopital St Andre, Germany Bordeaux; Mihaela Cordeanu, CHRU Strasbourg, Annette Adamczyk, Saskia Schnabl, Universitäts-Hautklinik Strasbourg; Francis Couturaud, Karine Lacut, CHRU Tübingen, Tübingen; Wail Al Ahmad, Heinz Weber, Sozial- Hopital Cavale Blanche, Brest; Laure De Dedker, François stiftung Bamberg, Bamberg; Christoph Axthelm, Praxis Xavier Piloquet, Hôpital Nord Laennec, Saint Herblain; Axthelm, Pirna; Rupert Bauersachs, Klinikum Darmstadt, Eric Decoulx, Centre Hospitalier de Tourcoing, Tour- Darmstadt; Klaus Bergmann, Nägelsbachstraße 49 c, coing; Benoit Derrien, Centre Hospitalier, Le Mans Erlangen; Ulrich Beschorner, Matthias Knittel, Herzzen- Cedex 9; Jean-Marc Diamand, Centre De Medecine trum Bad Krozingen, Bad Krozingen; Karl-Heinz Binias, Vasculaire, Grenoble; Antoine Diard, 25 Route De Martin Pasligh, Ameos Klinikum Schönebeck, Schönebeck; Creon, Langoiran; Youssef Douadi, Centre Hospitalier Mehmet Boral, Friederike, Girke, Vivantes Klinikum De Saint Quentin, St Quentin; Stephane Dupas, Neukölln, Berlin; Hermann Bratsch, P7, 13, Mannheim; Santhi Samy Modeliar Remond, Marie-Antoinette Gunter Brauer, Berliner Str. 158, Cottbus; Sebastian Sevestre, CHU Amiens Picardie - Hôpital Sud, Burghard, Carl-von-Basedow-Klinikum, Merseburg; Amiens Cedex 1; Stéphane Edhery, Hôpital Saint Christiane Demann, Carsten Rennebaum, Praxis Emter/ Antoine, Paris; Nicolas Falvo CHU Dijon Service De Rennebaum/Demann, Hannover; Anita Demmig, Linde- Medecine Interne, Dijon; Claudia Farcas Taralunga, nallee 7, Hoppegarten; Ulrich Eberlein, Ketschengasse 22- Hôpital Saint Charles, Toul; Emile Ferrari, Hôpital 24, Coburg; Frank Enger, MVZ Nibelungen (Enger), Pasteur, Nice; Catherine Gaillard, 14 rue Maurice Biebesheim; Jens, Eschenburg, Jens-Uwe Eschenburg, Devillers, Peronne; Damien Garrigues, Clinique Neubrandenburg; Lutz Forkmann, MVZ Polymed Monie, Villefranche-de-Lauragais; Jean Luc Gillet, Forkmann, Chemnitz; Jürgen Frank, In der Schaf 14, 51BIS Avenue Professeur Tixier, Bourgoin Jallieux; Baesweiler; Holger Freischmidt, Martin Gassauer, Pascal Giordana, L'empire 29, Boulevard Dubouchage, BGU Ludwigshafen, Ludwigshafen; Ilona Fritsche, Nice; Claire Grange, Denis Vital-Durand, Hopital Cornelia Kubicek–Hofmann, Vivantes Klinikum im Lyon Sud, Pierre Benite; Frédérick Grare, Espace Friedrichshain, Berlin; Mark-Claudius Goebels, Marien- Medical Torremila, Perpignan; Amine Hadj Henni, Hospital Euskirchen, Euskirchen; Stephan Guggenbichler, CHU Robert-Debré, Reims; Simone Heuser, Jeannot Stephan Guggenbichler, Frauenstrasse 17, München; Dirk Schmidt, Centre Hospitalier Universitaire, Clermont Härtel, Klinikum Detmold, Detmold; Karsten Hartmann, Ferrand; Valérie Hidden-Henic, Centre Hospitalier de Venenzentrum Freiburg, Freiburg; Peter, Heilberger, Wattrelos, Wattrelos; Delphine Hottin, Centre Hospi- Heilberger, Schweinauer Hauptstr. 12, Nürnberg; Andreas talier Docteur Schaffner, Lens Cedex; Bernard Imbert, Heinsius, Jüdisches Krankenhaus Berlin, Berlin; Michael Gilles Pernod, Hopital Nord Michallon, La Tronche; Held, Steffen Schnupp, Klinikum Coburg, Coburg; Georg Daniel Jakob, Clinique Générale, Valence; Vincent Herman, Am Finkenhügel 1, Osnabrück; Jörg Herold, Jacquinandi, Maison Médicale de Spécialistes, Trelaze; Universitätsklinikum Magdeburg, Magdeburg; Frank Christine Jurus, Clinique du Tonkin, Villeurbanne; Hertrich, Am Bahnhof 6, Lebach; Henrike Hommel, Amelie Lacoste, 10, rue Abert Camus, Pontarlier; Jean- Privatklinik Robert Schindlbeck, Herrsching; Guntram Pierre Laroche, Médipole, Avignon; Myriam Martin, 13 Hütte, Christoph Kalka, Marienhospital Brühl, Brühl; Rue De La Poste, Annecy; Cyrille Mazollier, Pôle Médical, Katja Jungandreas, Mathias Ramthor, Vivantes Humboldt Saint Laurent de la Salanque; Tahar Mersel, 2 rue Klinikum, Berlin; Jan Karcher, Nicolas Werner, Klinikum Egassiairal, Narbonne; Gilles Miserey, 55 Rue Ludwigshafen, Ludwigshafen; Susanne Karl-Wollweber, Gambetta, Rambouillet; Charles Nedey, Clinique Du St. Marien-Hospital Lünen, Lünen; Dag-Alexander Tonkin, Villeurbanne; Monica Nou, Isabelle Quere, Keilhau, Lerchenfeld 14, Hamburg; Kerstin Kittel, Naum- Hopital Saint Eloi, Montpellier; Pierre Ouvry, Clinique burger Str. 74, Weißenfels; Tanja Knolinski, Bethesda MEGIVAL, St Aubin sur Scie; Bernadette Peuch, 1 bis Krankenhaus Bergedorf, Hamburg; Christina Köhler, Place Mendes France, Castelnau le lez; Olivier Pichot, Sebastian Werth, Uniklinik Dresden, Dresden; Ute Centre de Médecine Vasculaire, Grenoble; Veyre Kopplin, Kirchplatz 10a, Bad Salzungen; Ines Körner, Poulain, 19 rue Vimaine, Vienne; Patrick Ray, Hopital Kathrin Wittig, Praxis Dres. Wittig/Rühlmann/Körner, Thonon, Paris; Abed Rifai, Centre Hospitalier, Arras; Leipzig; Knut Kröger, Theodoros Moysidis, Helios Klinik Pierre-Marie Roy, Angers; Jean-Claude Saby, Clinique Krefeld, Krefeld; Ulf Kroschel, Herzklinik Ulm, Ulm; du Tondu, Bordeaux; Frédéric Simon, 51 avenue Jean Matthias Leschke, Tim zur Nieden, Klinikum Esslingen, JAURES, Lyon; Eliane Simonot-Lalandec, 60 bis rue Esslingen; Gerhard Lübbert, Krankenhaus Neu-Mariahilf de Camtimpré, Cambrai; Dominique Stephan, CHRU GmbH, Göttingen; Arno Lutz, Petra Wucherpfennig, Strasbourg, Strasbourg; Anne Tissot, Clinique du Vinzenzkrankenhaus Hannover, Hannover; Geert-H TONKIN, Villeurbanne; Hubert Vodoungnon, Hôpital Marencke, Bremerhaven; Kai Mortensen, Michael Reppel, de Dunckerque, Dunkerque. Universitätsklinikum Lübeck, Lübeck; Heike Nelles, Agnelli et al. Thrombosis Journal (2015) 13:41 Page 9 of 13

Lindenaustr. 5, Altenburg; Kay Nestler, Kleiststr. 5, Vascolare, Roma; Andrea Arone, Francesco Perticone, Grimma; Axel Neumeister, Alexander Schlosser, Helios Angela Sciacqua, Unità Operativa di Malattie Cardiovas- Klinikum Erfurt, Erfurt; Wolfram Oettler, Carolusstr. 214, colari Policlinico Mater Domini di Catanzaro, Catanzaro; Görlitz; Ilka Ott, Deutsches Herzzentrum München, Giovanni Asaro, Mario Bellisi, U.O. Chirurgia Vascolare, München; Annegret Otto, Alexander-Puschkin-Platz 4c, Palermo; Maria Teresa Attanzio, Antonio Pinto, U.O.C. Riesa; Astrid Pertermann, Polimed Leipzig, Leipzig; Rahel Medicina Vascolare, Palermo; Valerio Attinasi, Enrico Pfister, Kaiser-Joseph-Str. 262, Freiburg; Lukas Pindur, Cillari, Sabrina Sorvillo, P.O. Cervello, Palermo; Alberto Gefäßpraxis Leverkusen – Linz, Leverkusen; Siamak Pour- Balbarini, Claudia Santini, Caterina Violo, U.O. Cardio- hassan, Chirurgische Gemeinschaftspraxis, Klosterstr. 12, Angiologia Universitaria, Pisa; Elena Banfi, Corrado Oberhausen; Diethard Predel, Grimmelallee 2c, Nordhau- Lodigiani, Istituto di Ricovero e Cura a Carattere Scien- sen; Thomas Pudollek, Wiesenstr. 1, Bernsdorf; Dietrich tifico –Istituto Clinico Humanitas, Rozzano (MI); Doris Reimer, Julius-Lübke-Str. 13, Anderbeck; Cornelia Richter, Barcellona, Stefano Delpin, Silvia Marongiu, Medicina R 1, 2-3, Mannheim; Eberhad Rieker, Südstr. 29, Lauffen; interna 1 e emocoagulopati, Monserrato (Cagliari); Gabriele Rothenbücher, Zeppelinstraße 16, Dornstadt; Giovanni Barillari, Samantha Pasca, Azienda Ospedaliero Brigitte Rothhagen, Gothaer Str. 1, Waltershausen; Sim- Universitaria S. Maria della Misericordia, Udine; Claudia one Rudolff, Markus Stücker, Maria-Hilf-KH Bochum Bartolini, Paolo Verdecchia, Ospedale di Assisi, Assisi (Venenzentrum), Bochum; Andreas Schäfer, Kristina (PG); Mosè Bartone, Gerardo Mancuso, Unità Operativa Sonnenschein, Medizinische Hochschule Hannover, Complessa di Medicina Interna - Presidio Ospedaliero Hannover; Wolfgang Schafnitzl, Mönckebergstr. 18, Ham- “Giovanni Paolo II”, Lamezia Terme (CZ); Ignazio burg; Sebastian Schellong, Birgit Voigts, Krankenhaus Bellanuova, Salvatore Felis, Ospedale Garibaldi Centro – Dresden-Friedrichstadt, Dresden; Martin Schiller, Klini- Catania, CATANIA (Catania); Annamaria Bellizzi, Luca kum Ingolstadt, Ingolstadt; Thomas Schmeink, Praxis Masotti, AUSL 6 di Livorno, Cecina (LI); Marina Schmeink, Aachen; Henrik Schneider, Sana Hanse Klini- Bianchi, Anna Carugati, Ospedale Valduce, Como; kum Wismar, Wismar; Norbert Schön, Töginger Str. 27, Giuseppe Bianchini, Giorgio Guarnera, Istituto Dermo- Mühldorf; Matthias Schulze, Asklepios Klinikum patico dell’Immacolata, ROMA; Benedetta Boari, Schwalmstadt, Schwalmstadt; Udo Sechtem, RBK Stutt- Massimo Gallerani, Mauro Pasin, Arcispedale Sant’Anna gart, Stuttgart; Sabine Sedl, Feldstraße 23a, Schönberg; di Ferrara, Ferrara; Cristiano Bortoluzzi, Roberto Parisi, Harriet Simone Werno, Parcside medical center - Harriet U.O. Semplice dipartimentale di Angiologia, Venezia; Simone Werno, Nürnberg; Jörg Stachowitz, St. Johannis- Caterina Brucoli, Giuseppe Palasciano, U.O. Medicina stift Paderborn, Paderborn; Marcus Thieme, Medinos Interna Ospedaliera “Ferranini-Pende”, Bari; Giuseppe Klinik Sonneberg, Sonneberg; Christiane Tiefenbacher, Camporese, Chiara Tonello, Azienda Ospedaliera di Marien-Hospital Wesel, Wesel; Dimitrios Tsantilas, Padova, Padova; Lucia Canafoglia, Serena Rupoli, Clinica Halderstr. 23, Augsburg; Petra Vieth, Marienhospital di Ematologia, Torrette di Ancona (ANCONA); Emilia Steinfurt, Steinfurt; Jürgen vom Dahl, Katharina Cancellieri, Oriana Paoletti, Sophie Testa, AO Istituti Grün-Himmelmann, Krankenhaus St. Franziskus Ospitalieri di Cremona, Cremona; Anita Carlizza, Mönchengladbach, Mönchengladbach; Peter von Ospedale S. Giovanni dell’Addolorata, Roma; Marino Bilderling, Thordis von Maltik, Gefäßpraxis München Carnovali, Simona Sada, Anna Samaden, Azienda – Mietaschk, München; Katrin Weinrich, Klinikum Ospedaliera “Guido Salvini”, Milano; Chiara Casarsa, Augsburg, Augsburg; Marc Weyer, Eduardus Kranken- Filippo Mearelli, Giulia Pivetti, S.C. Clinica Medica, haus, Köln, Marc Weyer, DRK Kamillus Klinik, Trieste; Roberto Catalini, Oriana Zingaretti, Medicina Asbach; Peter Wirtz, Kreiskrankenhaus Mechernich, Vascolare, Torrette di Ancona (ANCONA); Stefania Mechernich; Ina Wittig, Käthe-Kollwitz-Str. 9, Leipzig; Cavazza,BenildeCosmi,AngiologiaeMalattiedella Petra Zierock, Vivantes Klinikum Spandau, Berlin. Coagulazione “Marino Golinelli”,Bologna;Caterina Cenci, Domenico Prisco, Elena Silvestri, S.O.D. Patologia Italy Medica, Firenze (FI); Fabrizio Ceresa, Francesco Patanè, Walter Ageno, Monica Caprioli, Elena Rancan, U.O. Azienda Ospedaliera Ospedali Riuniti, Messina; Antonio Medicina Interna I, Varese; Giancarlo Agnelli, Francesco Ciampa, Valeria Siniscalchi, Centro Emostasi, Avellino; Guercini, Valeria Mommi, Dipartimento di Medicina Tiziana Ciarambino, Giuseppe De Bartolomeo, Ospedale Interna e Vascolare, Perugia (PG); Maria Amitrano, Ferdinando Veneziale, Isernia; Michele Clemente, Presidio Francesca Cannavacciuolo, Dipartimento Medicina Ospedaliero “Madonna delle Grazie” - Matera, Matera; Interna, Avellino; Maurizio Amore, Sebastiano D'Antoni, Franco Conti, Laura Paiella, A.O. San Camillo-Forlanini, Ospedale Vittorio Emanuele II, Catania; Ermanno Angel- Roma; Maria D’Avino, U.O.C. Medicina Interna ad indir- ini, Saverio La Forgia, Cardiologia-UTIC, Brindisi (BR); izzo Angiologico e Cerebrovascolare, Napoli; Aldo D'Ales- Pier Luigi Antignani, Giuseppe Calandra, Centro sandro, Marisa Placentino, Vito Sollazzo, Ospedale Civile Agnelli et al. Thrombosis Journal (2015) 13:41 Page 10 of 13

di San Severo (FG), San Severo (FG); Armando D'Angelo, Presidio Ospedaliero Ferrarotto, Catania; Cinzia Nitti, Silvana Viganò, Servizio Coagulazione ed Unità Ricerca Milena Pennacchioni, Aldo Salvi, Medicina Internistica e Trombosi Istituto Scientifico Universitario, Milano; Paolo Sub-Intensiva, Torrette di Ancona (ANCONA); Oliviero De Campora, Raffaele Sangiuolo, Ospedale Buonconsiglio Olivieri, Federica Tosi, Francesco Zorzi, Ospedale Borgo Fatebenefratelli, Napoli; Stefano De Franciscis, Raffaele Roma, Verona; Maicol Onesta, U.O.C. di Medicina Interna, Serra, Università degli Studi Magna Grecia di Catanzaro, Fabriano (AN); Valeria Pagliara, Sabina Villalta, U.O. Medi- Catanzaro; Egidio De Gaudenzi, SOC Medicina Interna, cina Interna 1, Treviso; Giancarlo Paolucci, Salvatore Domodossola (VB); Fernando De Santis, Giovanni Carlo Severino, Casa di Cura Privata “Villa Serena”, CASSINO Piccinni, Presidio Ospedaliero Francesco Ferrari-Casarano, (FR); Francesca Pierri, Vitantonio Russo, U.O.C. Cardiolo- Lecce; Italo De Tommaso, U.O. Cardiologia, A.O.R. San gia, Taranto; Attilia Maria Pizzini, A.O. Arcispedale “Santa Carlo, Potenza; Letizia Di Francesco, Giovanni Maria Maria Nuova”, Reggio Emilia; Roberto Quintavalla, Vincentelli, U.O.S. Reparto di Breve Osservazione, Roma; Pasquale Rubino, Strutt. Complessa di Medicina interna ad Rosario Di Maggio, Giorgia Saccullo, Sergio Siragusa, U.O. indirizzo angiologico e coagulativo, Parma; Luigi Ria, Presi- Ematologia con trapianto, Palermo; Pierpaolo Di Micco, dio Ospedaliero “Sacro Cuore di Gesù”, Lecce; Alessandro Andrea Fontanella, Ospedale Buonconsiglio Fatebenefra- Schenone, S.C. Medicina Interna II, Genova; Cosimo telli, Napoli; Dario Di Michele, U.O. Medicina Interna - Strafino, U.O. Medicina Interna, Termoli (CB); Pietro P.O.“G. Mazzini”, Teramo; Giovanni Di Minno, Antonella Tropeano, Centro Diagnosi e Cura Malattie Tromboembo- Tufano, Università Federico II di Napoli, Napoli; Marcello liche Venose, Pordenone; Alfredo Vetrano, Azienda Ospe- DiNisio,EttorePorreca,DipartimentodiMedicinae daliera S. Anna e S. Sebastiano di Caserta, Caserta; Nello Scienze dell’invecchiamento, Chieti; Francesca Donadio, Zanatta, U.O. Semplice Dipartimentale di Angiologia – Davide Imberti, UOC di Medicina Interna ERI, Piacenza; Dipartimento di Medicina, Vittorio Veneto (TV). Iolanda Enea, Azienda Ospedaliera S. Anna e S. Sebastiano di Caserta, Caserta; Fabio Fabbian, Roberto Manfredini, Spain Marco Pala, Arcispedale Sant’Anna di Ferrara, Ferrara; Maria Dolores Adarraga Cansino, Hospital de Montilla, Anna Falanga, Viola Milesi, Centro Di Emostasi e Trom- Córdoba; Juan Alonso Gutierrez, Francisco Arnaiz de las bosi, Bergamo; Valerio Fiore, Salvatore Santo Signorelli, Revillas, Hospital Valdecilla, Cantabria; Cristina Amado Ospedale Garibaldi Centro – Catania, CATANIA Fernández, Núria Calvo Mijares, Hospital de Sierrallana, (Catania); Elio Franco, Giorgio Giudice, U.O. Chirurgia Cantabria; Maria Ángeles Blanco-Molina, Hospital U. Vascolare, Benevento; Gabriele Frausini, Marina Rovinelli, Reina Sofia Córdoba; Maria Angelina Garcia, Dolores U.O.C. MEDICINA INTERNA, FANO (PU); Mariella Joya Seijo, Hospital Rey Juan Carlos, Móstoles; Rocío Ar- Fuorlo, Raffaele Landolfi, Tiziana Morretti, U. O. anda Blazquez, Juan-Bosco López-Sáez, Hospital U. Complessa Clinica Medica, Roma; Susanna Gamberini, Puerto Real, Puerto Real (Cádiz); Eduardo Arellano Mauro Pasin, Raffaella Salmi, Arcispedale Sant’Anna di Rodrigo, Jaume Villalta Blanch, Hospital Clínic i Provin- Ferrara, Ferrara; Angelo Ghirarduzzi, Maria Rosaria cial, Barcelona; Arola Armengou Arxe, Fernando García- Veropalumbo, A.O. Arcispedale “Santa Maria Nuova”, Bragado Dalmau, Hospital U. Dr. Josep Trueta, Girona; ReggioEmilia;MauroGhizzi,CarloPepe,AziendaUnità Aitor Ballaz Quincoces, Amaia García Loizaga, Hospital Sanitaria Locale di Modena, Sassuolo Modena; Francesca de Galdakao, Galdakao; José Luis Beato Pérez, Hospital Gianniello, Ida Martinelli, Fondazione IRCCS Ca’ Granda, de Hellín, Hellín (Albacete); Pedro Bedate Díaz, Andrés MILANO;DianaIrinaIosub,FrancoPiovella,FONDA- Quezada Loaiza, Hospital Central de Asturias, OVIEDO ZIONE IRCCS S. MATTEO DI PAVIA, PAVIA; Ercole (PRINCIPADO DE ASTURIAS); Marc Cairols Castel- Iozzi, Agostino Talerico, Unità Operativa di Angiologia, lote, Centro Médico Delfos, Barcelona; Inma Cañas Crotone (KR); Micaela La Regina, Francesco Orlandini, Alcántara, Meritxell Lluís Padierna, Fundació Hospital Struttura Complessa Medicina Interna, La Spezia; Letizia de Granollers, Granollers; Marina Carrasco Expósito, Marconi, Antonio Palla, U.O. Pneumologia 1 Universitaria, Juan Antonio Millón Caño, Hospital de la Santa Creu i Pisa; Rossella Marcucci, Daniela Poli, Dipartimento di Sant Pau Barcelona; Amparo Carrasco Mas, Fernando Malattie Aterotrombotiche, Firenze (FI); Riccardo Mar- Cereto Castro, Clínica Quirón, Barcelona; Rafael Castro- gheriti, Gianpaolo Sala, OSPEDALE GRASSI, ROMA; deza Sanz, Juan Ortiz de Saracho, Hospital El Bierzo, Alfonso Marra, Cardiologia UTIC, Piedimonte Matese - León; Elena Cisneros de la Fuente, Hospital Son Llàtzer, Caserta; Fausto Marrocco, Ospedale Scolastica di Cassino, Palma de Mallorca; Cristina de Ancos Aracil, Justo Ruiz Cassino; Elisabetta Sara Montagna, Franco Silvestris, Ruiz, Hospital Universitario de Fuenlabrada, Madrid; Simona Vallarelli, U.O. MEDICINA INTERNA UNIVERSI- Maria Dolores de Daborenea González, Alfonso Fernán- TARIA “MICHELE BUFANO”, Bari; Lucio Mos, Valeria dez Iglesias, Hospital U. de Cruces, Bizkaia; Javier de la Rossetto, Dipartimento Di Emergenza, San Daniele del Fuente Aguado, Lucia González González, Hospital Friuli (UD); Francesco Mugno, Michelangelo Di Salvo, POVISA, Vigo; Maria del Carmen Fernández-Capitán, Agnelli et al. Thrombosis Journal (2015) 13:41 Page 11 of 13

Alicia Lorenzo Hernández, Hospital U. La Paz, Madrid; Raimundo Tirado Miranda, Hospital Infanta Margarita, Jorge del Toro Cervera, Gloria Pérez Rus, Hospital G. U. Cabra Córdoba; Esther Usandizaga de Antonio, Hospital Gregorio Marañón, Madrid; Juan Luis Delgado Bregel, Sant Joan Despí - Moisès Broggi, St. Joan Despí. Hospital Río Carrión, Palencia; Florentino Díez Fernán- dez, Emilio-Antonio Santalla Valle, Complejo Asistencial Switzerland Universitario de León, León; Teresa Elias Hernández, Martin Banyai, Luzerner Kantonspital, Luzern; Ulrich Luis Jara Palomares, Hospital Virgen del Rocío Frank, Gian Reto Jörg, Kantonspital Graubünden, Chur; SEVILLA; Ramón Ferri Bataler, José Antonio Nieto Christina Jeanneret, Kantonsspital Bruderholz, Bruder- Rodríguez, Hospital Virgen de la Luz, Cuenca; José holz; Daniel Staub, Universitätsspital Basel, Basel. María García García, Manuel Ángel Villanueva Montes, Hospital San Agustín, Áviles (Asturias); José Ramón United Kingdom González Porras, Hospital U. de Salamanca, Salamanca; Sam Ackroyd, Bradford Royal Infirmary, Bradford; María Guil García, Carlos Maria San Román Terán, Gaurav Agarwal, Ben Mearns, East Surrey Hospital, Red- Hospital Comarcal de la Axarquía, Málaga; Elena hill; Raza Alikhan, University Hospital Wales, Cardiff; Hernando López, Alejandra Roncero Lázaro, Hospital Allameddine Allameddine, The Royal Oldham Hospital, San Pedro, La Rioja; María Jesús Jaras, Hospital de Manchester; Faris Al-Refaie, The Princess Alexandra Cantoblanco, Madrid; David Jiménez Castro, Hospital Hospital NHS Trust, Essex; Christopher Arden, Park Ramón y Cajal, Madrid; Rafael Jiménez-Rodríguez Surgery, Chandlers Ford; Antony Austin, The Meadows Madridejos, José María Pedrajas Navas, Hospital Clínico Surgery, Ilminster; Ameet Bakhai, Barnet Hospital, San Carlos, Madrid; Ramón Lecumberri, Nicolás Martí- Barnet; Thomas Barton, Hayder Ewad, Neath Port nez, Clínica Universitaria de Navarra, Navarra; Genoveva Talbot Hospital, Port Talbot; Richard Body, Jecko Tha- Teresa López Castellanos, Luis Manzano Espinosa, Hos- chil, Manchester Royal Infirmary, Manchester; Joseph pital Ramón y Cajal, Madrid; Luciano López Jiménez, Chacko, Royal Bournemouth Hospital, Bournemouth; Hospital U. Reina Sofia, Córdoba; Olga Madridano Deepak Chandra, University Hospital of North Stafford- Cobo, Hospital Infanta Sofía, Madrid; Carmen Mainez shire NHS Trust, Stoke-on-Trent; Freda Charters, Burn- Saiz, Yolanda Romero Pizarro, Hospital Puerta de field Medical Practice, Inverness; Alistair Church, Hierro, Madrid; Pablo Javier Marchena Yglesias, Parc Frances McGrane, Western Infirmary, Glasgow; John Sanitari Sant Joan de Déu, Sant Boi de llobregat; Mar Clements, The Elmwood Surgery, Belfast; Piers Clifford, Martín del Pozo, Hospital Infanta Sofía, San Sebastián Wycombe Hospital, Wycombe; Dominic Cox, North- de los Reyes; Leonardo Melibovsky, Emilia Solé Altar- ampton General Hospital, Northampton; Matthew riba, Hospital del Mar, Barcelona; Manuel Monreal Crouch, The Practice of Health, Barry; Mark Crowther, Bosch, Hospital Germans Trias i Pujol, Badalona; Rafael Worcestershire Royal Hospital, Worcester; Emyr Davies, Monte Secades, Hospital Universitario Lucus Augustí, Waterfront Medical Centre, Barry; Mark Davies, West Lugo; José Maria Mora Luján, Antoni Riera Mestre, Cross Medical Centre, Swansea; Sameh Dimitri, Count- Hospital Universitari de Bellvitge, Barcelona; Pedro ess of Chester Hospital, Chester; Anja Drebes, Royal Moral Moral, José Antonio Todolí Parra, Hospital U. La Free Hospital, London; Simon Franklin, Budleigh Salter- Fe, VALENCIA; Aurora Moreno Flores, Juan Francisco ton Medical Centre, Devon; Jacob George, Nicola Irvine, Sánchez Muñoz-Torrero, Hospital San Pedro de Alcán- Ninewells Hospital, Dundee; Hagen Gerofke, Basildon tara, Cáceres; Francisco José Muñoz Rodríguez, Hospital University Hospital, Essex; Christopher Gibbs, North de Mollet, Mollet del Vallès (Barcelona); Manuel J. Devon District Hospital, Barnstaple; Teik Goh, The Núñez Fernández, Complejo Hospitalario de Pontevedra, Garth Surgery, Cleveland; Sunil Gupta, Eastbourne PONTEVEDRA; Estefanía Oncala Sibajas, Mercedes Va- District General and Conquest Hospital, Eastbourne; Jon quero de Sedas, Hospital Virgen de la Macarena, Sevilla; Holmes, Bronglais General Hospital, Aberystwith; Ewart Pedro Parra Caballero, Hospital La Princesa, Madrid; Jackson-Voyzey, Axbridge & Wedmore Research Prac- Isaac Pons Martín del Campo, Hospital d'Igualada, Igua- tice, Axbridge; Nick Jones, St Chad's Surgery, Radstock; lada; José Portillo Sánchez, Hospital G. U. Ciudad Real, Arun Kallat, Royal Bolton Hospital, Bolton; Patrick Kerr, Ciudad Real; Alberto Rivera Gallego, Iria Villaverde Ál- The Wall House Surgery, Surrey; Patrick Kesteven, New- varez, CHUVI - Hospital Xeral de Vigo, VIGO (Ponteve- castle upon Tyne Hospital Trust, Newcastle upon Tyne; dra); Eva Maria Rodríguez Beltrán, Demetrio Sánchez Tristan Lench, Severnbank Surgery, Lydney; William Fuentes, Complejo Hospitalario de Ávila, Ávila; Vanessa Lester, Gillian Lowe, University Hospital Birmingham, Roldán Schilling, Hospital Morales Messeguer, Murcia; Birmingham; Martin Lewis, The Queen Elizabeth Julio Sánchez Álvarez, Gregorio Tiberio López, Hospital Hospital NHS Foundation Trust, Norfolk; Terry McCor- Virgen del Camino, Pamplona; José Maria Suriñach Car- mack, Whitby Group Practice, Whitby; Andrew alt, Hospital Universitario Vall d'Hebrón, Barcelona; McCoye, Ecclesfield Group Practice, Sheffield; Andrew Agnelli et al. Thrombosis Journal (2015) 13:41 Page 12 of 13

Moriarty, Craigavon Area Hospital, Belfast; Wendy Author details 1 Morris, The Birches, Solihull; Bethan Myers, Lincoln University of Perugia, Santa Maria della Misericordia Hospital, Perugia, Italy. 2Herzzentrum Ludwigshafen Med. Klinik B, Ludwigshafen, Germany. County, Lincoln; Mekkali Narayanan, George Eliot 3Klinikum Darmstadt GmbH, Darmstadt, Center of Thrombosis and Hospital NHS Trust, Nuneaton; New Oo, Huddersfield Hemostasis, University of Mainz, Mainz, Germany. 4Center of Thrombosis and 5 Royal Infirmary, Huddersfield; Matthew Reed, Royal Haemostasis, University of Mainz, Mainz, Germany. Daiichi Sankyo Europe GmbH, Munich, Germany. 6CHU Saint-Etienne Hopital Nord, Saint Etienne Infirmary of Edinburgh, Edinburgh; Peter Rose, Warwick Cedex 2, France. 7Hospital Universitari Germans Trias i Pujol, Barcelona, Spain. Hospital, Warwick; Khalid Saja, Queen's Hospital, 8Charité – Universitätsmedizin Berlin, Berlin, Germany. 9King’s College, Guys Romford; Muttuswamy Sivakumaran, Peterborough City and St Thomas’ Hospitals NHS Foundation Trust, Westminster Bridge Road, London SE1 7EH, UK. Hospital, Peterborough; Mamta Sohal, Ealing Hospital, Southall; Gary Solomons, Parkwood Surgery, Hemel Received: 15 June 2015 Accepted: 12 October 2015 Hempstead; Sayed J. Sultanzadeh, Doncaster Royal Infirmary, Doncaster; Tamsin Venton, Teign Estuary Med- ical Group, Glendevon Medical Centre, Teignmouth; John References Wakeling, Ely Bridge Surgery, Cardiff; Ceri Walby, Clifton 1. Oger E. Incidence of venous thromboembolism: a community-based study Surgery, Cardiff; Michael Waldron, Enchord Limited, in Western France. EPI-GETBP study group. Groupe d'Etude de la Thrombose de Bretagne Occidentale. Thromb Haemost. 2000;83(5):657–60. Cornwall; Simon Watt, Wythenshawe hospital, Manches- 2. Cohen AT, Agnelli G, Anderson FA, Arcelus JI, Bergqvist D, Brecht JG, et al. ter; William Willcock, Rolle Medical Partnership, Venous thromboembolism (VTE) in Europe. The number of VTE events and Exmouth; Azhar Zafar, Danes Camp Medical Centre, associated morbidity and mortality. Thromb Haemost. 2007;98(4):756–64. 3. Spencer FA, Emery C, Lessard D, Anderson F, Emani S, Aragam J, et al. The Northampton. Worcester Venous Thromboembolism study: a population-based study of the clinical epidemiology of venous thromboembolism. J Gen Intern Med. Abbreviations 2006;21(7):722–7. doi:10.1111/j.1525-1497.2006.00458.x. VTE: Venous thromboembolism; PE: Pulmonary embolism; DVT: Deep vein 4. Martinez C, Cohen AT, Bamber L, Rietbrock S. Epidemiology of first and thrombosis; UFH: Unfractionated heparin; LMWH: Low molecular weight recurrent venous thromboembolism: a population-based cohort study in heparin; VKA: Vitamin K antagonist; INR: International normalization ratio; patients without active cancer. Thromb Haemost. 2014;112(2):255–63. QoL: Quality of life; HR-QoL: Health related quality of life; CV: Cardiovascular; doi:10.1160/TH13-09-0793. CRO: Contact research organization; PACT-Q2: Perception of anticoagulant 5. Kearon C, Gent M, Hirsh J, Weitz J, Kovacs MJ, Anderson DR, et al. A treatment questionnaire 2; Veines-QoL/Sym: Venous Insufficiency comparison of three months of anticoagulation with extended Epidemiological and Economic Study; PEmb-QoL: Pulmonary Embolism anticoagulation for a first episode of idiopathic venous thromboembolism. Quality of Life; AE: Adverse event; CI: Confidence interval. N Engl J Med. 1999;340(12):901–7. doi:10.1056/nejm199903253401201. 6. Konstantinides SV, Torbicki A, Agnelli G, Danchin N, Fitzmaurice D, Galie N, Competing interests et al. 2014 ESC guidelines on the diagnosis and management of acute – Giancarlo Agnelli (GA), Rupert Bauersachs (RB), Alexander T. Cohen (ATC), pulmonary embolism. Eur Heart J. 2014;35(43):3033 69. doi:10.1093/ Anselm K. Gitt (AKG), Patrick Mismetti (PM), Manuel Monreal (MM), and eurheartj/ehu283. 69a-69k. Stefan N. Willich (SNW) have received research support and/or honoraria for 7. Hutten BA, Prins MH. Duration of treatment with vitamin K antagonists in lectures from a number of pharmaceutical companies including Daiichi symptomatic venous thromboembolism. The Cochrane database of systematic Sankyo, the sponsor of the registry. Eva-Maria Fronk (EMF), Petra Laeis (PL), reviews. 2006(1):Cd001367. doi:10.1002/14651858.CD001367.pub2. Wolf-Peter Wolf (WPW) are employed by Daiichi Sankyo Europe GmbH. 8. Kearon C, Kahn SR, Agnelli G, Goldhaber S, Raskob GE, Comerota AJ. The members of the Steering Committee received honoraria and travel Antithrombotic therapy for venous thromboembolic disease: American reimbursements from Daiichi Sankyo Europe GmbH for their participation in college of chest physicians evidence-based clinical practice guidelines (8th Steering Committee Meetings. Edition). Chest. 2008;133(6 Suppl):454s–545s. doi:10.1378/chest.08-0658. 9. Schulman S, Granqvist S, Holmstrom M, Carlsson A, Lindmarker P, Nicol P, et al. The duration of oral anticoagulant therapy after a second Authors’ contributions episode of venous thromboembolism. The Duration of anticoagulation All authors have contributed to the design of the registry. EMF is responsible trial study group. N Engl J Med. 1997;336(6):393–8. doi:10.1056/ for the analysis of data. ATC, AKG, PL and WPW drafted the manuscript nejm199702063360601. based on the protocol and all other authors revised the article for important 10. Ansell J, Hirsh J, Hylek E, Jacobson A, Crowther M, Palareti G. Pharmacology intellectual content. All authors have finally approved the version to be and management of the vitamin K antagonists: American college of chest published. Apart from the selection of the countries, all design aspects were physicians evidence-based clinical practice guidelines (8th Edition. Chest. decided by the scientific Steering Committee and executed by independent 2008;133(6 Suppl):160s–98s. doi:10.1378/chest.08-0670. Contract Research organizations. The members of the Steering Committee 11. Kearon C, Akl EA, Comerota AJ, Prandoni P, Bounameaux H, Goldhaber SZ, received honoraria for their advice in the planning of the Registry. et al. Antithrombotic therapy for VTE disease: Antithrombotic therapy and prevention of Thrombosis, 9th ed: American college of chest physicians Acknowledgement evidence-based clinical practice guidelines. Chest. 2012;141(2 The authors acknowledge the substantial contribution of Dr. Markus Suppl):e419S–94S. doi:10.1378/chest.11-2301. Schwertfeger (Daiichi Sankyo) for his input into the design and setup of the 12. Mavrakanas T, Bounameaux H. The potential role of new oral anticoagulants registry. Furthermore we are indebted to all investigators across Austria, in the prevention and treatment of thromboembolism. Pharmacol Ther. France, Germany, Italy, Spain, Switzerland and the UK who have made this 2011;130(1):46–58. doi:10.1016/j.pharmthera.2010.12.007. registry possible. A full list of the PREFER in VTE investigators is given in the 13. Weitz JI, Eikelboom JW, Samama MM. New antithrombotic drugs: Appendix. Editorial assistance during the development of this manuscript Antithrombotic therapy and prevention of Thrombosis, 9th ed: American was provided by Paul Barlass and Matthew Bexon of in Science college of chest physicians evidence-based clinical practice guidelines. Communications, Springer Healthcare. This assistance was funded by Daiichi Chest. 2012;141(2 Suppl):e120S–51S. doi:10.1378/chest.11-2294. Sankyo Europe GmbH, Munich, Germany. 14. Keeley T, Al-Janabi H, Lorgelly P, Coast J. A qualitative assessment of the content validity of the ICECAP-A and EQ-5D-5L and their appropriateness Funding for use in health research. PLoS One. 2013;8(12), e85287. doi:10.1371/ Daiichi Sankyo Europe GmbH, Zielstattstrasse 48, 81379 Munich, Germany. journal.pone.0085287. Agnelli et al. Thrombosis Journal (2015) 13:41 Page 13 of 13

15. Bauersachs R, Berkowitz SD, Brenner B, Buller HR, Decousus H, Gallus AS, et al. Oral rivaroxaban for symptomatic venous thromboembolism. N Engl J Med. 2010;363(26):2499–510. doi:10.1056/NEJMoa1007903. 16. Buller HR, Prins MH, Lensin AW, Decousus H, Jacobson BF, Minar E, et al. Oral rivaroxaban for the treatment of symptomatic pulmonary embolism. N Engl J Med. 2012;366(14):1287–97. doi:10.1056/NEJMoa1113572. 17. Samsa G, Matchar DB, Dolor RJ, Wiklund I, Hedner E, Wygant G, et al. A new instrument for measuring anticoagulation-related quality of life: development and preliminary validation. Health Qual Life Outcomes. 2004;2:22. doi:10.1186/1477-7525-2-22. 18. Kahn SR, Lamping DL, Ducruet T, Arsenault L, Miron MJ, Roussin A, et al. VEINES-QOL/Sym questionnaire was a reliable and valid disease-specific quality of life measure for deep venous thrombosis. J Clin Epidemiol. 2006;59(10):1049–56. doi:10.1016/j.jclinepi.2005.10.016. 19. Klok FA, Cohn DM, Middeldorp S, Scharloo M, Buller HR, van Kralingen KW, et al. Quality of life after pulmonary embolism: validation of the PEmb-QoL Questionnaire. J Thromb Haemost. 2010;8(3):523–32. doi:10.1111/j.1538- 7836.2009.03726.x. 20. Tri-london.ac.uk. GARFIELD-VTE Registry Thrombosis Research Insitute, Providing Excellence in Thrombosis Research. 2015. http://www. tri-london.ac.uk/garfield-vte Accessed 27 May 2015 21. Monreal M, Suarez C, Fajardo JA, Barba R, Uresandi F, Valle R, et al. Management of patients with acute venous thromboembolism: findings from the RIETE registry. Pathophysiol Haemost Thromb. 2003;33(5-6):330–4. doi:83823.

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